2-phenanthrenyl carbapenem antibacterial agents

ABSTRACT

Carbapenems of the formula ##STR1## are useful antibacterial agents.

BACKGROUND OF THE INVENTION

The present invention relates to antibacterial agents of the carbapenemclass, in which the 2-position sidechain is characterized by aphenanthrene moiety, substituted by various neutral substituents, asdescribed in more detail further below.

Thienamycin was an early carbapenem antibacterial agent having a broadspectrum; it has the following formula: ##STR2## Later, N-formimidoylthienamycin was discovered; it has the formula: ##STR3##

The 2-phenanthrenyl-carbapenems of the present invention are notcharacterized by a broad antibacterial spectrum such as that ofthienamycin or N-formimidoyl thienamycin. Rather, their spectrum ofactivity is largely limited to gram positive microorganisms, especiallymethicillin resistant Staphylococcus aureus (MRSA), methicillinresistant Staphylococcus epidermidis (MRSE), and methicillin resistantcoagulase negative Staphylococci (MRCNS). The antibacterial compounds ofthe present invention thus comprise an important contribution to therapyof these difficult to control pathogens. Moreover, there is anincreasing need for agents effective against such pathogens (MRSA/MRCNS)which are at the same time safe, i.e., free from undesirable toxic sideeffects. No β-lactam antibacterial has yet been found which meets theserequirements. And, the current agent of choice, vancomycin, aglycopeptide antibacterial, is experiencing an ever increasing amount ofresistance in the MRSA/MRCNS pathogens.

More recently, carbapenem antibacterial agents have been described whichhave a 2-substitutent which is an aryl moiety optionally substituted by,e.g., aminomethyl and substituted aminomethyl. These agents aredescribed in U.S. Pat. Nos. 4,543,257 and 4,260,627 and have theformula: ##STR4##

However, there is no description or suggestion of a phenanthrenyl2-substituent such as characterizes the compounds of the presentinvention, nor is there any suggestion of the suprisingly betteranti-MRSA/MRCNS activity of the compounds of the present invention.

EP-A-0277 743 describes a particular class of compounds of the formula:##STR5## but this limited teaching in no way suggests the totallydifferent compounds of the present invention, nor their surprisinglybetter anti-MRSA/MRCNS activity.

SUMMARY OF INVENTION

The present invention provides novel carbapenem compounds of theformula: ##STR6## wherein: R is H or CH₃ ;

R¹ and R² are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂--, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂ CHCH(OH)--, F₃CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;

R^(a) are independently selected from the group consisting of hydrogenand the radicals set out below, provided that not more than four R^(a)radicals are other than hydrogen:

(a) a trifluoromethyl group: --CF₃ ;

(b) a halogen atom: --Br, --Cl, --F, or --I;

(c) C₁ -C₄ alkoxy radical: --OC₁₋₄ alkyl, wherein the alkyl isoptionally mono-substituted by R^(q), where

R^(q) is a member selected from the group consisting of --OH, --OCH₃,--CN, --C(O)NH₂, --OC(O)NH₂, CHO, --OC(O)N(CH₃)₂, --SO₂ NH₂, --SO₂N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F, --CF₃, --COOM^(a) (where M^(a) ishydrogen, alkali metal, methyl or phenyl), tetrazolyl (where the pointof attachment is the carbon atom of the tetrazole ring and one of thenitrogen atoms is mono-substituted by M^(a) as defined above) and --SO₃M^(b) (where M^(b) is hydrogen or an alkali metal);

(d) a hydroxy group: --OH;

(e) a carbonyloxy radical: --O(C═O)R^(s), where

R^(s) is C₁₋₄ alkyl or phenyl, each of which is optionallymono-substituted by R^(q) as defined above;

(f) a carbamoyloxy radical: --O(C═O)N(R^(y))R^(z) where

R^(y) and R^(z) are independently H, C₁₋₄ alkyl (optionallymono-substituted by R^(q) as defined above), together a 3- to 5-memberedalkylidene radical to form a ring (optionally substituted with R^(q) asdefined above) or together a 2- to 4-membered alkylidene radical,interrupted by --O--, --S--, --S(O)-- or --S(O)₂ -- to form a ring(where the ring is optionally mono-substituted with Rq as definedabove);

(g) a sulfur radical: --S(O)_(n) --R^(s) where n=0-2, and R^(s) isdefined above;

(h) a sulfamoyl group: --SO₂ N(R^(y))R^(z) where R^(y) and R^(z) are asdefined above;

(i) azido: N₃

(j) a formamido group: --N(R^(t))(C═O)H, where

R^(t) is is H or C₁₋₄ alkyl, and the alkyl thereof is optionallymono-substituted by R^(q) as defined above;

(k) a (C₁ -C₄ alkyl)carbonylamino radical: --N(R^(t))(C═O)C₁₋₄ alkyl,where R^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above;

(l) a (C₁ -C₄ alkoxy) carbonylamino radical: --N(R^(t))(C═O)OC₁₋₄ alkyl,where R^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above;

(m) a ureido group: --N(R^(t))(C═O)N(R^(y))R^(z) where R^(t), R^(y) andR^(z) are as defined above;

(n) a sulfonamido group: --N(R^(t))SO₂ R^(s), where R^(s) and R^(t) areas defined above;

(o) a cyano group: --CN;

(p) a formyl or acetalized formyl radical: --(C═O)H or --CH(OCH₃)₂ ;

(q) (C₁ -C₄ alkyl)carbonyl radical wherein the carbonyl is acetalized:--C(OCH₃)₂ C₁₋₄ alkyl, where the alkyl is optionally mono-substituted byR^(q) as defined above;

(r) carbonyl radical: --(C═O)R^(s), where R^(s) is as defined above;

(s) a hydroximinomethyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group: --(C═NOR^(z))R^(y) whereR^(y) and R^(z) are as defined above, except they may not be joinedtogether to form a ring;

(t) a (C₁ -C₄ alkoxy)carbonyl radical: --(C═O)OC₁₋₄ alkyl, where thealkyl is optionally mono-substituted by R^(q) as defined above;

(u) a carbamoyl radical: --(C═O)N(R^(y))R^(z) where R^(y) and R^(z) areas defined above;

(v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical in whichthe nitrogen atom may be additionally substituted by a C₁ -C₄ alkylgroup: --(C═O)--N(OR^(y))R^(z) where R^(y) and R^(z) are as definedabove, except they may not be joined together to form a ring;

(w) a thiocarbamoyl group: --(C═S)N(R^(y))(R^(z)) where R^(y) and R^(z)are as defined above;

(x) carboxyl: --COOM^(b), where M^(b) is as defined above;

(y) thiocyanate: --SCN;

(z) trifluoromethylthio: --SCF₃ ;

(aa) tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above;

(ab) an anionic function selected from the group consisting of:phosphono [P═O(OM^(b))₂ ]; alkylphosphono {P═O(OM^(b))--[O(C₁ -C₄alkyl)]}; alkylphosphinyl [P═O(OM^(b))--(C₁ -C₄ alkyl)]; phosphoramido[P═O(OM^(b))N(R^(y))R^(z) and P═O(OM^(b))NHR^(x) ]; sulfino (SO₂ M^(b));sulfo (SO₃ M^(b)); acylsulfonamides selected from the structuresCONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂ NM^(b)CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where

R^(x) is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatichydrocarbon group having 5 or 6 ring atoms, in which a carbon atom isthe point of attachment, in which one of the carbon atoms has beenreplaced by a nitrogen atom, in which one additional carbon atom isoptionally replaced by a heteroatom selected from O or S, and in whichfrom 1 to 2 additional carbon atoms are optionally replaced by anitrogen heteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), as defined above; M^(b) is as defined above;and R^(y) and R^(z) are as defined above;

(ac) C₅ -C₇ cycloalkyl group in which one of the carbon atoms in thering is replaced by a heteroatom selected from O, S, NH or N(C₁ -C₄alkyl) and in which one additional carbon atom may be replaced by NH orN(C₁ -C₄ alkyl), and in which at least one carbon atom adjacent to eachnitrogen heteroatom has both of its attached hydrogen atoms replaced byone oxygen thus forming a carbonyl moiety and there are one or twocarbonyl moieties present in the ring;

(ad) C₂ -C₄ alkenyl radical, optionally mono-substituted by one of thesubstituents (a) to (ac) above and phenyl which is optionallysubstituted by R^(q) as defined above;

(ae) C₂ -C₄ alkynyl radical, optionally mono-substituted by one of thesubstituents (a) to (ac) above;

(af) C₁ -C₄ alkyl radical;

(ag) C₁ -C₄ alkyl mono-substituted by one of the substituents (a)-(ac)above;

(ah) a 2-oxazolidinonyl moiety in which the point of attachment is thenitrogen atom of the oxazolidinone ring, the ring oxygen atom isoptionally replaced by a heteroatom selected from --S-- and NR^(t)(where R^(t) is as defined above) and one of the saturated carbon atomsof the oxazolidinone ring is optionally mono-substituted by one of thesubstituents (a) to (ag) above;

M is selected from:

(i) hydrogen;

(ii) a pharmaceutically acceptable esterifying group or removablecarboxyl protecting group; or

(iii) an alkali metal or other pharmaceutically acceptable cation.

DETAILED DESCRIPTION OF THE INVENTION

The manufacture of compounds of Formula I may be carried out in athree-stage synthesis scheme followed by a final step which allows forthe removal of any protecting groups. The objective of the firstsynthetic stage is to produce a base phenanthrene compound which may beconverted to the two-position substituent of the carbapenem of FormulaI. The objective of the second synthetic stage is to attach the basephenanthrene to the carbapenem. Finally, the objective of the thirdsynthetic stage is to substitute the phenanthrene with the desiredR^(a). This third synthetic stage may be performed after the firstsynthetic stage or during or after the second synthetic stage accordingto the nature of the various R^(a).

Flow Sheet A demonstrates a suggested first stage synthesis. Flow SheetsB and C demonstrate two alternative second stage syntheses. The thirdsynthesis varies according to the selected R^(a).

The suggested first synthesis herein, Flow Sheet A, is generally knownas a Pschorr Synthesis to produce phenanthrenes. This synthesis isdescribed in P. H. Leake, Chem. Rev., 56 27 (1956); D. F. De Tar, Org.React., 9 409 (1957); E. A. Nodiff et. al., J. Med. Chem. 14 921 (1971);and E. A. Nodiff et. al., J. Med. Chem. 18 1011 (1975). These referencesare incorporated by reference. Other phenanthrene syntheses aredescribed in A. J. Floyd, S. F. Dyke, and S. E. Ward, Chem. Rev., 76 509(1976); F. B. Mallory and C. Mallory, Org. React. 30 1 (1984); G.Zanardi et. al., Synthesis 333 (1988); and V. Snieckus et. al.,Tetrahedron Lett. 43 5459 (1988); also incorporated by reference.

Referring to Flow Sheet A, the 4-bromobenzoaldehyde Al is reacted in aPerkin Condensation with p-nitrophenylacetic acid A2 in acetic anhydrideat about 40° C. using triethylamine as a catalyst. The resultingcompound A3 contains a nitro group which can be reduced to an amine inorder to close the phenanthrene ring. This is accomplished by heatingcompound A3 to about 100° C. in water with NaOH and FeSO₄.7H₂ O toproduce compound A4, an amino-carboxylate. The amino-carboxylate A4 maybe subsequently closed to phenanthrene A5 in a two-step reaction.Firstly, amino-carboxylate A4 is reacted with isoamyl nitrite and HCl inethanol at about 0° C. Secondly, this reaction mixture is added to asuspension of copper in a solution of NaH₂ PO₂.H₂ O and H₂ SO₄ in waterat about 40° C. The resultant phenanthrene A5 is the object compound ofFlow Sheet A. It may be substituted with R^(a) other than hydrogen asappropriate. However, using the starting materials shown, it must havecarboxyl in the 9-position. ##STR7##

A simple variation of Flow Sheet A will produce a 10-position carboxylsubstitution equivalent to compound A5. This variation requires that thefixed R^(a) substitution and the bromine substitution of compound A1 beremoved and placed on compound A2 with the bromine para to the aceticacid side-chain and meta to the nitro and to R^(a). Of course the R₄^(a) substitution of compound A2 should be placed on compound A1 leavingat least one position ortho to the aldehyde of A1 occupied by hydrogen.This interchange of substituents has the effect of rotating thephenanthrene to make what would have been the 9-position carbon of FlowSheet A, the 10-position carbon and thus making the 9-position carboxylsubstitution of Flow Sheet A, a 10-position carboxyl substitution.

The object compound of Flow Sheet A, phenanthrene A5, forms the nucleusof the 2-position substitution of the carbapenem compounds taughtherein. As such it is shown to be R^(a) substituted. However, it isimmediately clear to those skilled in the art that certain R^(a) listedabove, if substituted on A1 or A2 or both would not survive or permitthe synthesis to A5. Thus, where a certain R^(a) is desired on theposition-7 of compound A5 and this R^(a) is not compatible with thesynthesis scheme to produce A5, then a compatible precursor substituentmay be employed through the synthesis.

The identity of the precursor substituent employed is not crucial solong as it does not interfere with the synthesis to A5 and so long as itmay be thereafter converted to more desireable substitution. Preferredprecursor substituents are methyl, hydroxymethyl and protectedhydroxymethyl.

Thus, as to the R^(a) substituent on compound A5, it may be an R^(a)with or without protecting groups stable to the conditions of producingcompound A5 and stable to the conditions of subsequently adding A5 tothe carbapenem. Alternatively, it may be a stable precursor substituentwhich is stable to the conditions of making A5, which is optionallystable to the conditions of adding A5 to the carbapenem and which isconvertible to a desired R^(a) or to another precursor substituent.

Similarly to a precursor substituent, the 9- or 10-position carboxylsubstitution of compound A5 may be employed to add the desired R^(a) tothese positions. Where an R^(a) is desired in the 9- or 10-position,which is stable to the conditions of adding A5 to the carbapenem, thenthe carboxy may be replaced on A5 with this substitution by theappropriate chemistry. Where an R^(a) is desired in the 9- or10-position which is unstable to the chemistry of adding A5 to thecarbapenem, then the carboxyl must be converted to a stable precursorsubstituent such as t-butyldimethylsilyloxy-methyl.

As stated above, the second stage synthesis is to attach the basephenanthrene to the 2-position of the carbapenem. Employing phenanthreneA5, a starting material B1 for the suggested second stage synthesis maybe produced. Referring still to Flow Sheet A, and starting with A5, itis first necessary to convert the 9-position carboxyl to hydrogen, adesired R^(a) substituent, or a precursor substituent thereto which isstable to the reaction conditions of adding the phenanthrene to asubstituted azetidin-2-one precursor of the desired carbapenem. At-butyldimethylsilyloxymethyl precursor substituent may be obtained onthe 9-position of A5 in two steps. Firstly, carboxyl is reduced tohydroxymethyl by reacting A5 with borane in THF at 0° C. to RT.Secondly, the reaction product is isolated and reacted witht-butyldimethylsilyl chloride in dichloromethane with triethylamine and4-dimethylaminopyridine to produce protected phenanthrene B1. Withstable R^(a) or suitable precursor substituents therefor, phenanthreneB1 may be added to azetidin-2-one B2 in a Grignard reaction as shown inFlow Sheet B. The Grignard reaction requires that B1 be converted to aGrignard reagent by reaction with magnesium and 1,2-dibromoethane in THFfrom 20° C. to 60° C. and subsequently contacting B1 as a Grignardreagent with B2 in THF at from -70° C. to about 20° C. to produceazetidin-2-one B3 . Alternatively, B1 may be reacted witht-butyllithium, n-butyllithium, or the like in THF at from -78° to -50°C. followed by the addition of magnesium bromide to produce the sameGrignard reagent. R^(i) of B3 is in practice pyrid-2-yl but may clearlybe a variety of substituents including aromatic and heteroaromaticsubstituents. Further R^(i) might be for example phenyl, 2-pyrimidinylor 2-thiazolyl.

Azetidin-2-one B3 is an intermediate that may be ring closed to acarbapenem. It is on this intermediate that R^(a) or precursorsubstituent such as (t-butyldimethylsilyloxy)methyl may be modifiedwhere such modification is incompatible with the carbapenem nucleus. Forexample, a convenient reaction to remove the t-butyldimethylsilyl groupof B3 is to expose it to a dilute solution of sulfuric acid in methanolat 0° C. for from a few minutes to several hours. Flow Sheet B shows theresulting compound B3A. If the t-butyldimethylsilyl group was removedunder the same conditions after cyclization of B3 to a carbapenem, asubstantial portion of the carbapenem would be degraded and lost. Thus,modification of the precursor substituent in this instance andreplacement with another precursor substituent or even R^(a) is bestperformed before closing the carbapenem. Of course it is possible toremove the t-butyldimethylsilyl group in reduced yield after cyclizationof B3 to a carbapenem by reaction with tetra-n-butylammonium fluorideand acetic acid in THF.

Compound B3A may be ring closed to carbapenem B4 by refluxing in xylenewith a trace of p-hydroquinone for about 1 to 2 hours in an inertatmosphere. It is on this intermediate that final elaboration of R^(a)from a precursor substituent, e.g. hydroxymethyl, may be accomplished.Removal of the carboxyl and hydroxyl protecting groups then provides thefinal compound of Formula I. Such final elaboration and deprotection isdescribed in further detail below. ##STR8##

Flow Sheet C shows an alternative second stage synthesis, i.e.attachment of the base phenanthrene such as B1 to the 2-position of thecarbapenem. This synthesis involves a palladium catalyzed cross-couplingreaction between a carbapenem triflate and a suitably substitutedarylstannane, a process which is described in U.S. patent applicationSer. No. 485,096 filed Feb. 26, 1990, hereby incorporated by reference.In order to apply this synthesis, it is first necessary to modifybromophenanthrene B1 to the trimethylstannylphenanthrene C3. This isaccomplished by reacting B1 with t-butyllithium in THF at from -78° to-50° C. followed by the addition of trimethyltin chloride. This providesan intermediate from which the t-butyldimethylsilyl protecting group onthe 9-position hydroxymethyl substituent is removed by exposure totetra-n-butylammonium fluoride in THF yielding C3. Alternatively,bromophenanthrene B1 may be reacted with hexamethylditin in the presenceof a palladium (0) catalyst such astetrakis(triphenylphosphine)palladium in an inert solvent such astoluene at from 25° to 110° C. for from 0.25-24 hours to provide, afterremoval of the t-butyldimethylsilyl protecting group as described above,the same stannane C3. If the t-butyldimethylsilyl group was removed fromcarbapenem C4 under the same conditions, after attachment of thephenanthrene side-chain to the carbapenem, a much reduced overall yieldwould be obtained due to degradation of the carbapenem during suchremoval. Thus modification of the precursor substituent in this instanceand replacement with another precursor substituent or even R^(a) is bestperformed before attachment to the carbapenem. Referring to Flow SheetC, the 2-oxocarbapenam C1 is reacted with a suitabletrifluoromethanesulfonyl source, such as trifluoromethanesulfonicanhydride, trifluoromethanesulfonyl chloride and the like, in thepresence of an organic nitrogen base, such as triethylamine,diisopropylamine and the like, in polar aprotic solvent, such astetrahydrofuran or methylene chloride. An organic nitrogen base, such astriethylamine and the like, is then added to the reaction solutionfollowed immediately by a silylating agent, such as trimethylsilyltrifluoromethanesulfonate to provide intermediate C2. An aprotic polarcoordinating solvent, such as DMF, 1-methyl-2-pyrrolidinone and thelike, is added. This is followed by the addition of a palladiumcompound, such as tris(dibenzylideneacetone)dipalladium-chloroform,palladium acetate and the like, a suitably substituted phenylphosphine,such as tris(4-methoxyphenyl)phosphine, tris(2,4,6-trimethoxyphenyl)phosphine and the like, and the stannane C3. A metalhalide, such as lithium chloride, zinc chloride and the like, is addedand the reaction solution is allowed to warm and is stirred at asuitable temperature, such as 0° to 50° C. for from a few minutes to 48hours. The carbapenem C4 is obtained by conventionalisolation/purification methodology known in the art.

Generally speaking, the milder conditions of the synthesis shown in FlowSheet C allow for a wider range of functional groups R^(a) to be presentthan the synthesis illustrated in Flow Sheet B. However, in certaincases it is advantageous for the R^(a) substituent(s) of the stannane C3to be introduced in a protected or precursory form. Final elaboration ofR^(a) from a precursor substituent, e.g. hydroxymethyl, may beaccomplished on carbapenem intermediate C4. Removal of hydroxyl andcarboxyl protecting groups then provides the final compound of FormulaI. Such final elaboration and deprotection is described in furtherdetail below. ##STR9##

Azetidin-2-one B2, a pyridyl-thioester, is a well known compound in theproduction of carbapenems. Diverse synthetic schemes useful to make B2may be imagined by the skilled artisan. Particularly useful to theinstant invention is a synthetic scheme set out further in Flow Sheet Dbelow in which the symbol R is as defined above. The steps for preparingintermediate B2 are analogous to the procedures described, for example,in U.S. Pat. Nos. 4,260,627 and 4,543,257; L. D. Cama et al.Tetrahedron, 39, 2531 (1983); R. N. Guthikonda et al. J. Med. Chem., 30,871 (1987) hereby incorporated by reference. ##STR10##

The steps for preparing the 2-oxocarbapenam intermediate C1 are wellknown in the art and are explained in ample detail by D. G. Melillo etal., Tetrahedron Letters, 21, 2783 (1980), T. Salzmann et al., J. Am.Chem. Soc., 102, 6161 (1980), and L. M. Fuentes, I. Shinkai, and T. N.Salzmann, J. Am. Chem. Soc., 108, 4675 (1986). The syntheses are alsodisclosed in U.S. Pat. Nos. 4,269,772, 4,350,631, 4,383,946 and4,414,155 all assigned to Merck and Company, Inc. and herebyincorporated by reference.

The general synthesis description depicted above in the Flow Sheetsshows a protected 1-hydroxyethyl substitution on the 6-position of thecarbapenem. After final deprotection, a 1-hydroxyethyl substituent isobtained, which is preferred in most cases. However, it has been foundthat with certain 2-side-chain selections, the ultimate balance offavorable properties in the overall molecule may be enhanced byselection of the 6-(1-fluoroethyl) moiety instead. Preparation of6-fluoroalkyl compounds within the scope of the present invention iscarried out in a straightforward manner using techniques well known inthe art of preparing carbapenem antibacterial compounds. See, e.g., J.G. deVries et al., Heterocycles, 23 (8), 1915 (1985); BE 900 718 A(Sandoz) and Japanese Patent Pub. No. 6-0163-882-A (Sanruku Ocean).

In preferred compounds of Formula I, R¹ is hydrogen. More preferably, R¹is hydrogen and R² is (R)--CH₃ CH(OH)-- or (R)--CH₃ CH(F)--. In the mostpreferred case, R¹ is hydrogen and R² is (R)--CH₃ CH(OH)--. While R=H isusually preferred, there are instances in which R=CH₃ may provideimproved chemical stability, water solubility, or pharmacokineticbehavior. The substituent R=CH₃ may be of either configuration, i.e.,the α or β-stereoisomer. Additionally, in preferred compounds, at leastone R^(a) in the 1-, 9-, or 10-position of the phenanthrene is otherthan hydrogen. In the most preferred compounds, in total, up to twoR^(a) substituents in either the 1-, 9- or 10-position is other thanhydrogen.

Suitable R^(a) are described above in the text associated with FormulaI. Among preferred R^(a) are C₁₋₄ alkyl mono-substituted with hydroxy,such as, hydroxymethyl; formyl; carboxy, such as, --COOK; carbamoyl,such as, --CONH₂ ; hydroxoximinomethyl, such as, --CH═NOH or cyano.

In regard to this preferred substitution, the hydroxymethyl groups maybe obtained in the 9-and 10-positions of the phenanthrene as shown inFlow Sheets A and B. The hydroxymethyl may be obtained in any ofpositions 1, 5, 6, 7 or 8 as follows. Methyl, as a precursorsubstituent, is substituted on starting materials A1 and/or A2 in theappropriate positions by well known means and the starting materialsreacted to a corresponding methyl-substituted A5 according the FlowSheet A. At this point, the 9- or 10-position carboxy may be removedfrom methyl-substituted A5, if desired, by heating with copper powder ora copper salt such as CuCO₃ in a high boiling solvent such as quinoline.Subsequently, the methyl substituent of methyl-substituted A5 may beoxidized e.g. to carboxy with chromium trioxide or to bromomethyl withN-bromosuccinimide. This oxidation of the precursor substituent, methyl,is advantageously performed prior to substituting the phenanthrene onthe azetidin-2-one as the oxidizing conditions are incompatible witheither the azetidin-2-one or the subsequent carbapenem. The resultant 1,5, 6, 7 or 8 carboxy or bromomethyl substituted phenanthrene may befurther elaborated to obtain a corresponding "isomeric" B1. In the caseof the carboxy substituent, this is accomplished as previously describedin Flow Sheet A. In the case of the bromomethyl substituent, conversionto an isomeric B1 may be accomplished by a three-step sequence. Reactionof the bromomethyl compound with potassium acetate in DMF at 80° C.gives the corresponding acetoxymethyl compound. Removal of the acetategroup, e.g. by hydrolysis with methanolic sodium hydroxide or byreduction with diisobutylaluminium hydride in THF, gives thehydroxymethyl substituted compound which is converted to the isomeric B1by silylation with t-butyldimethylsilyl chloride, triethylamine and4-dimethylaminopyridine in dichloromethane. Further elaboration ofisomeric B1 according to Flow Sheet B produces a corresponding isomericB3, B3A and B4. Of course, the isomeric B4 is the hydroxymethyl of the1, 5, 6, 7 or 8 positions sought above.

The preferred formyl substitution on the phenanthrene may be obtainedfrom the hydroxymethyl substitution of B4 or isomeric B4 just describedby a Swern oxidation. For example, isomeric B4 is oxidized in methylenechloride at from -70° C. to room temperature employing oxalylchloride-dimethyl sulfoxide followed by triethylamine as the activeagent. Obviously, the position of the resultant formyl substitution willdepend upon the position of the hydroxymethyl substitution in isomericB4.

The preferred --CH═NOH substitution on the phenanthrene may beconveniently obtained from the formyl substitution just described. Thisis accomplished simply by exposing the formyl substituted compound tohydroxylamine in an appropriate solvent at room temperature.

The preferred cyano substitution on the phenanthrene may be obtainedfrom the --CH═NOH substitution just described. The --CH═NOH substitutedcompound is dehydrated with triflic anhydride and triethylamine in asolvent at -70° C.

The preferred --COOK substitution on the phenanthrene may be obtainedfrom the hydroxymethyl substituted B3A or isomeric B3A described above.For example, an isomeric B3A is oxidized with Jones reagent to convertthe hydroxymethyl substituent with the carboxylic acid group. Theoxidation with Jones reagent may be incompatible with the carbapenem andthus is optimally performed before ring closure. Prior to ring closure,the carboxylic acid group is protected as its allyl ester to permitcyclization of the carbapenem. Protection is carried out by alkylatingwith allyl bromide and triethylamine. Deprotection following cyclizationis carried out in a palladium catalyzed reaction, in a solutioncontaining potassium 2-ethylhexanoate, as described in McCombie andJeffrey, J. Org. Chem., 47, 2505 (1983). Deprotection in such a solutionyields the desired potassium salt.

The preferred carbamoyl substitution on the phenanthrene, may beobtained from B3A or "isomeric" B3A by oxidizing the hydroxymethyl groupwith Jones reagent to the corresponding carboxylic acid group asdescribed above. This carboxylic acid substituent is converted to thecarboxamide group, --CONH₂, by sequentially contacting with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,1-hydroxybenzotriazole, and ammonia in an organic solvent at roomtemperature. Substituted amides may of course be obtained by replacingammonia with the corresponding substituted amine. In contrast to thecarboxyl substitution, this carbamoyl group requires no protection forthe conditions of carbapenem cyclization.

Compounds substituted with the preferred R^(a) of Type II just describedmay also be obtained by employing the synthesis shown in Flow Sheet C.In this case, the synthetic transformations just described may becarried-out on intermediate C3 prior to attachment of the phenanthreneside chain to the carbapenem or on C4 after such attachment.

In the preparation methods described above, the carboxyl group at the3-position and the hydroxyl group at the 8-position of the carbapenemremain blocked by protecting groups until the penultimate product isprepared. Deblocking may be carried out in a conventional manner. Forcompounds prepared according to Flow Sheet B, deprotection may becarried out in a palladium catalyzed rection in a solution containingpotassium 2-ethylhexanoate and 2-ethylhexanoic acid or, alternatively,another suitable nucleophile such as pyrrolidine. Alternatively, forthose prepared via Flow Sheet C, deprotection is conducted sequentially.Thus, compound C4 is exposed initially to aqueous acidic conditions,acetic acid or dilute HCl or the like, in an organic solvent such astetrahydrofuran at 0° C. to ambient temperature for from a few minutesto several hours. The resulting desilylated carbapenem may be isolatedby conventional techniques, but is more conveniently taken into thefinal deprotection process. Thus, addition of an inorganic base such asNaHCO₃ or KHCO₃ and 10% Pd/C followed by hydrogenation provides for theremoval of the p-nitrobenzyl protecting group and the formation of thefinal compound of Formula I.

With reference to the above definitions, "alkyl" means a straight orbranched chain aliphatic hydrocarbon radical.

The term "heteroatom" means N, S, or O, selected on an independentbasis.

The term "heteroaryl" has been defined herein, in relation to the R^(x)group, to have a specific and limited meaning, being only monocyclic. Itis required that the monocyclic heteroaryl have at least one nitrogenatom, and optionally at most only one additional oxygen or sulfurheteroatom may be present. Heteroaryls of this type are pyrrole andpyridine (1N); and oxazole, thiazole or oxazine (1N+1O or 1S). Whileadditional nitrogen atoms may be present together with the firstnitrogen and oxygen or sulfur, giving, e.g., a thiadiazole (2N's+1S),the preferred heteroaryls are those where only nitrogen heteroatoms arepresent when there is more than one. Typical of these are pyrazole,imidazole, pyrimidine and pyrazine (2N's) and triazine (3N's).

The heteroaryl group of R^(x) is always optionally mono-substituted byR^(q), defined above, and substitution can be on one of the carbon atomsor one of the heteroatoms, although in the latter case certainsubstitutent choices may not be appropriate.

Listed in Tables I and II are specific compounds of the instantinvention:

                                      TABLE I                                     __________________________________________________________________________     ##STR11##                                                                                                         Ra                                       #  R   R.sup.1                                                                          R.sup.2   M   R.sup.a      position                                 __________________________________________________________________________    1  H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           OCH.sub.3    9,10                                     2  H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           OCH.sub.2 CO.sub.2 Na                                                                      1                                        3  H   H  (R)CH(OH)CH.sub.3                                                                       H   OCH.sub.2 CH.sub.2 OH                                                                      9                                        4  H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CF.sub.3     1                                        5  H   H  (R) CH(OH)CH.sub.3                                                                      Na.sup.+                                                                          F            1                                        6  H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          Cl           9                                        7  H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          Br           10                                       8  H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           F            1,7,9,10                                 9  H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          OH           9,10                                     10 CH.sub.3                                                                          H  (R)CH(OH)CH.sub.3                                                                       H   OCOCH.sub.3  9                                        11 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          OCONH.sub.2  9                                        12 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          SCH.sub.3    1                                        13 H   H  (R)CH(F)CH.sub.3                                                                        K.sup.+                                                                           SOCH.sub.3   1                                        14 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           SO.sub.2 CH.sub.3                                                                          1                                        15 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          SCH.sub.2 CH.sub.2 OH                                                                      1                                        16 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          SOCH.sub.2 CH.sub.2 OH                                                                     9                                        17 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          SCH.sub.2 CONH.sub.2                                                                       1                                        18 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          SO.sub.2 NH.sub.2                                                                          1                                        19 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          SO.sub.2 N(CH.sub.3).sub.2                                                                 7,9                                      20 H   H  CF.sub.2 CH.sub.3                                                                       K.sup.+                                                                           NHCHO        10,8                                     21 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           NHCOCH.sub.3 1                                        22 H   H  (R)CH(OH)CH.sub.3                                                                       H   NHCO.sub.2 CH.sub.3                                                                        10                                       23 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           NHSO.sub.2 CH.sub.3                                                                        1                                        24 H   H  (R)CH(F)CH.sub.3                                                                        K.sup.+                                                                           CN           1                                        25 H   H  (R)CH(F)CH.sub.3                                                                        K.sup.+                                                                           CHO          1                                        26 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           COCH.sub.3   10                                       27 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          COCH.sub.2 OH                                                                              9                                        28 CH.sub.3                                                                          H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CHNOH        6                                        29 H   H  (R)CH(OH)CH.sub.3                                                                        Na.sup.+                                                                         CHNOCH.sub.3 1                                        30 CH.sub.3                                                                          H  (R)CH(OH)CH.sub.3                                                                       H   CHNOCH.sub.2 CO.sub.2 H                                                                    9                                        31 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CHNOCMe.sub.2 CO.sub.2 Na                                                                  7                                        32 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CHNOCMe.sub.2 CO.sub.2 Me                                                                  1                                        33 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CO.sub.2 CH.sub.2 CH.sub.2 OH                                                              1                                        34 H   H  (R)CH(F)CH.sub.3                                                                        K.sup.+                                                                           CONH.sub.2   1,9                                      35 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CONHCH.sub.3 9                                        36 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CON(CH.sub.3).sub.2                                                                        10                                       37 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CONHCH.sub.2 CN                                                                            1                                        38 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CONHCH.sub.2 CONH.sub.2                                                                    1                                        39 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CONHCH.sub.2 CO.sub.2 H                                                                    1                                        40 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CONHOH       1                                        41 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CONHOCH.sub.3                                                                              9                                        42 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          tetrazolyl   1                                        43 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CO.sub.2 Na  9                                        44 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          SCF.sub.3    1                                        45 H   H  (R)CH(OH)CH.sub.3                                                                       H   PO.sub.3 NaH 1                                        46 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CONHSO.sub.2 Ph                                                                            10                                       47 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CONHSO.sub.2 NH.sub.2                                                                      1                                        48 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           SO.sub.3 Na  1                                        49 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          SO.sub.2 NHCN                                                                              1                                        50 H   H  (R)CH(F)CH.sub.3                                                                        Na.sup.+                                                                          SO.sub.2 NHCONH.sub.2                                                                      1                                        51 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CHCHCN       1                                        52 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CHCHCONH.sub.2                                                                             1                                        53 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CHCHCO.sub.2 Na                                                                            9                                        54 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CCCONH.sub.2 1                                        55 CH.sub.3                                                                          H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CCCN         9                                        56 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CH.sub.2 OH  5                                        57 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CH.sub.2 N.sub.3                                                                           9                                        58 H   H  (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CH.sub.2 CO.sub.2 Na                                                                       9                                        59 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CN           1                                        60 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CN           7                                        61 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CN           8                                        62 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CN           9                                        63 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CN           10                                       64 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CHO          5                                        65 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CHO          6                                        66 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CHO          7                                        67 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CHO          8                                        68 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CHO          9                                        69 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CHO          10                                       70 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CONH.sub.2   1                                        71 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CONH.sub.2   7                                        72 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CONH.sub.2   8                                        73 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CONH.sub.2   9                                        74 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CONH.sub.2   10                                       75 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CHNOH        1                                        76 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CHNOH        7                                        77 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CHNOH        8                                        78 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CHNOH        9                                        79 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CHNOH        10                                       80 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CH.sub.2 OH  7                                        81 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           CH.sub.2 OH  9                                        82 H   H  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           H            --                                       __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________     ##STR12##                                                                    #   R  R.sup.1                                                                           R.sup.2   M   R.sup.a                                              __________________________________________________________________________    1   H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           1-F   9-CH.sub.2 OH                                  2   H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           1-F   9-CHO                                          3   H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           1-SOCH.sub.3                                                                        9-CHO                                          4   H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           1-SOCH.sub.3                                                                        7-CHO                                          5   H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           1-CN  7-SOCH.sub.3                                   6   H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           1-CONH.sub.2                                                                        9-CH.sub.2 OH                                  7   H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           1-CONH.sub.2                                                                        9-SOCH.sub.3                                   8   H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           1-CN  7-CH.sub.2 OH                                  9   H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           9-CHO 10-OH                                          10  H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           1-CONH.sub.2                                                                        9-CHO                                          11  H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           1-CN  9-CO.sub.2 K                                   12  H  H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                           1-CONH.sub.2                                                                        10-OH                                          __________________________________________________________________________

The carbapenem compounds of the present invention are useful per se andin their pharmaceutically acceptable salt and ester forms in thetreatment of bacterial infections in animal and human subjects. The term"pharmaceutically acceptable ester or salt" refers to those salt andester forms of the compounds of the present invention which would beapparent to the pharmaceutical chemist, i.e., those which are non-toxicand which would favorably affect the pharmacokinetic properties of saidcompounds, their palatability, absorption, distribution, metabolism andexcretion. Other factors, more practical in nature, which are alsoimportant in the selection, are cost of the raw materials, ease ofcrystallization, yield, stability, hygroscopicity, and flowability ofthe resulting bulk drug. Conveniently, pharmaceutical compositions maybe prepared from the active ingredients in combination withpharmaceutically acceptable carriers. Thus, the present invention isalso concerned with pharmaceutical compositions and methods of treatingbacterial infections utilizing as an active ingredient the novelcarbapenem compounds of the present invention.

The pharmaceutically acceptable salts referred to above may take theform --COOM. The M may be an alkali metal cation such as sodium orpotassium. Other pharmaceutically acceptable cations for M may becalcium, magnesium, zinc, ammonium, or alkylammonium cations such astetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium,meglumine, triethanolhydroammonium, etc.

The pharmaceutical acceptable esters of the novel carbapenem compoundsof the present invention are such as would be readily apparent to amedicinal chemist, and include, for example, those described in detailin U.S. Pat. No. 4,309,438, Column 9, line 61 to Column 12, line 51,which is incorporated herein by reference. Included within suchpharmaceutically acceptable esters are those which are hydrolyzed underphysiological conditions, such as pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, and those described in detail inU.S. Pat. No. 4,479,947, which is incorporated herein by reference.

The novel carbapenem compounds of the present invention may take theform COOM, where M is a readily removable carboxyl protecting group.Such conventional blocking groups consist of known ester groups whichare used to protectively block the carboxyl group during the synthesisprocedures described above. These conventional blocking groups arereadily removable, i.e., they can be removed, if desired, by procedureswhich will not cause cleavage or other disruption of the remainingportions of the molecule. Such procedures include chemical and enzymatichydrolysis, treatment with chemical reducing or oxidizing agents undermild conditions, treatment with a transition metal catalyst and anucleophile, and catalytic hydrogenation. Examples of such esterprotecting groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethyl,allyl, benzyl, t-butyl, trichloroethyl, silyl such as trimethylsilyl,trimethylsilylethyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl,p-methoxyphenyl and 4-pyridylmethyl.

The compounds of the present invention are valuable antibacterial agentsactive against various Gram-positive and to a lesser extentGram-negative bacteria and accordingly find utility in human andveterinary medicine. The antibacterials of the invention are not limitedto utility as medicaments; they may be used in all manner of industry,for example: additives to animal feed, preservation of food,disinfectants, and in other industrial systems where control ofbacterial growth is desired. For example, they may be employed inaqueous compositions in concentrations ranging from 0.1 to 100 parts ofantibiotic per million parts of solution in order to destroy or inhibitthe growth of harmful bacteria on medical and dental equipment and asbactericides in industrial applications, for example in waterbasedpaints and in the white water of paper mills to inhibit the growth ofharmful bacteria.

The compounds of this invention may be used in any of a variety ofpharmaceutical preparations. They may be employed in capsule, powderform, in liquid solution, or in suspension. They may be administered bya variety of means; those of principal interest include: topically orparenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents.Alternatively, the active ingredient may be in powder form forreconstitution, at the time of delivery, with a suitable vehicle, suchas sterile water. Topical applications may be formulated in hydrophobicor hydrophilic bases as ointments, creams, lotions, paints, or powders.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated as well as the route andfrequency of administration, the parenteral route by injection beingpreferred for generalized infections. Such matters, however, are left tothe routine discretion of the therapist according to principles oftreatment well known in the antibacterial art. Another factorinfluencing the precise dosage regimen, apart from the nature of theinfection and peculiar identity of the individual being treated, is themolecular weight of the chosen species of this invention.

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from 0.1% to 99% of active material, the preferredrange being from about 10-60%. The composition will generally containfrom about 15 mg to about 1500 mg of the active ingredient; however, ingeneral, it is preferable to employ a dosage amount in the range of fromabout 250 mg to 1000 mg. In parenteral administration, the unit dosageis usually the pure compound I in sterile water solution or in the formof a soluble powder intended for solution.

The preferred method of administration of the Formula I antibacterialcompounds is parenteral by i.v. infusion, i.v. bolus, or i.m. injection.

For adults, 5-50 mg of Formula I antibacterial compounds per kg of bodyweight given 2, 3, or 4 times per day is preferred. Preferred dosage is250 mg to 1000 mg of the Formula I antibacterial given two (b.i.d.)three (t.i.d.) or four (q.i.d.) times per day. More specifically, formild infections a dose of 250 mg t.i.d. or q.i.d. is recommended. Formoderate infections against highly susceptible gram positive organisms adose of 500 mg t.i.d. or q.i.d. is recommended. For severe,life-threatening infections against organisms at the upper limits ofsensitivity to the antibiotic, a dose of 1000 mg t.i.d. or q.i.d. isrecommended.

For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 timesper day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usuallyrecommended.

Antibacterial compounds of Formula I are of the broad class known ascarbapenems or 1-carbadethiapenems. Naturally occuring carbapenems aresusceptible to attack by a renal enzyme known as dehydropeptidase (DHP).This attack or degradation may reduce the efficacy of the carbapenemantibacterial agent. The compounds of the present invention, on theother hand, are significantly less subject to such attack, and thereforemay not require the use of a DHP inhibitor. However, such use isoptional and contemplated to be part of the present invention.Inhibitors of DHP and their use with carbapenem antibacterial agents aredisclosed in the prior art [see European Patent Applications No.79102616.4 filed Jul. 24, 1979 (Patent No. 0 007 614); and No.82107174.3, filed Aug. 9, 1982 (Publication No. 0 072 014)].

The compounds of the present invention may, where DHP inhibition isdesired or necessary, be combined or used with the appropriate DHPinhibitor as described in the aforesaid patents and publishedapplication. Thus, to the extent that the cited European patentapplications 1. define the procedure for determining DHP susceptibilityof the present carbapenems and 2. disclose suitable inhibitors,combination compositions and methods of treatment, they are incorporatedherein by reference. A preferred weight ratio of Formula I compound: DHPinhibitor in the combination compositions is about 1:1. A preferred DHPinhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid or a useful salt thereof.

EXAMPLE 1 ##STR13## α-(2-nitrophenyl)-p-bromocinnamic acid (1)

A solution of 4-bromobenzaldehyde (27.75 g, 0.150 mol),2-nitrophenylacetic acid (27.18 g, 0.150 mol) and triethylamine (21.0ml, 0.150 mol) in 150 ml of acetic anhydride was heated at 40° C. for 38hours and then poured into 900 ml of water and stirred until the organiclayer solidified. The solid was isolated by filtration and dried invacuo to yield 48.3 g (92%) of the title compound as a tan solid whichwas sufficiently pure to use directly in the next reaction.

¹ H-NMR (300 MHz,d₆ -acetone): δ 7.06 (d,J=8.6 Hz,2H), 7.25 (m,1H), 7.39(d,J=8.6 Hz,2H), 7.65 (m,2H), 7.87 (s,1H,HC═C), 8.2 (m,1H).

EXAMPLE 2 ##STR14## Sodium α-(o-aminophenyl)-p-bromocinnamate (2)

To a mixture of FeSO₄.7H₂ O (163 g, 0.586 mol) in 180 ml of water wasadded 720 ml of 2.5N NaOH and the mixture was stirred and heated at 80°C. A solution of cinnamic acid derivative 1 (20.40 g, 0.05859 mol) in180 ml of 0.5N NaOH was added dropwise. After the addition was complete,the temperature was increased to 100° C. and maintained for 30 min. Themixture was filtered while hot, and the filtrate was allowed to coolgradually to room temperature. The resulting solid was isolated byfiltration to yield, after drying in vacuo, 12.1 g (61%) of the titlecompound as a tan solid which was used in the next reaction withoutpurification. ¹ H-NMR (300 MHz, 2:1 D₂ O/CD₃ CN): δ 6.95-7.15 (m,3H),7.18 (d,J=7.3 Hz,2H), 7.39 (t, J=7.6 Hz, 1H), 7.53 (d, J=7.3 Hz,2H),7.72 (s, CH═C, 1H).

EXAMPLE 3 ##STR15## 3-Bromophenanthrene-9-carboxylic acid (3)

A suspension of the amino-carboxylate 2 (13.3 g, 39.1 mmol) in 155 ml ofethanol was cooled to 0° C. and isoamyl nitrite (18.0 ml, 134 mmol) wasadded followed by dropwise addition of 15% ethanolic HCl (125 ml) during1 hour. The resulting brown slurry was stirred at 0° C. for 2 hoursmore, and was then added gradually to a vigorously stirred suspension ofcopper powder (1.8 g) in a solution of NaH₂ PO₂.H₂ O (41.4 g, 391 mmol)and conc. H₂ SO₄ (3 drops) in 63 ml of water which was maintained at 40°C. After the addition was complete, the mixture was stirred at 40° C.for 1 hour and was then cooled to 0° C. and the solid was isolated byfiltration, washing with water. Drying in vacuo gave 9.9 g of a brownsolid which was taken-up in CH₂ Cl₂ -THF, filtered to remove someinorganic material, and evaporated to yield 7.28 g (62%) of the titlecompound as a tan solid. This compound was used in the next reactionwithout purification.

¹ H-NMR (300 MHZ, d₆ -acetone): δ 7.75 (m, 2H), 7.82 (dd, J=8.5, 1.8 Hz,1H), 8.07 (d, J=8.5 Hz, 1H), 8.58 (s, 1H), 8.84 (m, 1H), 9.00 (s, 1H),9.01 (m, 1H).

EXAMPLE 4 ##STR16## 3-Bromo-9-(hydroxymethyl)-phenanthrene (4)

A solution of 3-bromo-phenanthrene-9-carboxylic acid (6.27 g, 20.8 mmol)in 100 ml of THF was cooled to 0° C. and a solution of borane in THF(1.0M, 25 ml, 25 mmol) was added dropwise. The cooling bath was removed,and the solution was stirred at room temperature for 19 hours and wasthen quenched by the cautious addition of methanol (25 ml). The solutionwas evaporated to dryness in vacuo and the residue was dissolved inmethanol - CH₂ Cl₂ (1:1) and again evaporated. After one repetition ofthis dissolution-evaporation process, 5.96 g (100%) of the titlecompound was obtained as a brown solid which was used in the nextreaction without purification.

¹ H-NMR (300 MHz, CDCl₃): δ 5.17 (s, 2H), 7.6-7.8 (m, 5H), 8.12 (m, 1H),8.61 (m, 1H), 8.76 (s, 1H).

EXAMPLE 5 ##STR17##3-Bromo-9-(t-butyldimethylsilyloxymethyl)-phenanthrene (5)

To a solution of 3-bromo-9-(hydroxymethyl) phenanthrene, 4 (5.96 g, 20.8mmol) and t-butyldimethylsilyl chloride (4.7 g, 31 mmol) in 100 ml ofCH₂ Cl₂ and 20 ml of THF was added triethylamine (4.9 ml, 35 mmol)followed by 4-dimethylaminopyridine (250 mg, 2.05 mmol). After stirringat room temperature for 20 hours, the solution was poured into 300 ml ofethyl ether and washed successively with sat. NH₄ Cl, sat. NaHCO₃, H₂ O,and brine. Drying (Na₂ SO₄) and evaporation gave a brown solid which waspurified by flash chromatography through 400 g of silica gel (1:4 CH₂Cl₂ -hexane) to yield 7.23 g (87%) of the title compound as a paleyellow solid.

¹ H-NMR (300 MHz, CDCl₃): δ 0.172 (s, 6H), 0.995 (s, 9H), 5.21 (s, 2H),7.66 (m, 3H), 7.76 (d, J=8.5 Hz, 1H), 7.81 (s, 1H), 8.01 (m, 1H), 8.62(m, 1H), 8.79 (d, J=1.71 Hz, 1H).

FAB-MS: m/e=400,402 (M⁺).

EXAMPLE 5A ##STR18## 3-Trimethylstannyl-9-(hydroxymethyl)-phenanthrene(5A)

Bromophenanthrene 5 (1.02 g, 2.5 mmol) was dissolved in anhydrous THF(15 mL) and cooled to -78° C. under nitrogen. To this stirred solutionwas added a solution of t-Butyllithium in pentane (2.2 equiv.; 5.5 mmol;3.0 mL). After 30 minutes at -78° C., the reaction was warmed to -50° C.for 20 minutes, after which time Me₃ SnCl (1.1 equiv.; 2.75 mmol; 548mg) was added as a solid. The cold bath was removed and the reactionallowed to reach ambient temperature. After 75 minutes, the reaction wasquenched with water. The solvent was removed in vacuo and the residualdissolved in Et₂ O. Washing with water and brine was followed by dryingover MgSO₄, filtering and removal of solvent. The residual was dissolvedin anhydrous THF and treated with a 1.0M solution of n-Bu₄ NF in THF(1.1 equiv.; 2.75 mmol; 2.75 mL) at ambient temperature for 5 minutes.Quenching the reaction with saturated NH₄ Cl was followed by removal ofthe solvent in vacuo. The residual was dissolved in EtOAc and washedwith water and brine, dried (MgSO₄), filtered and the solvent removed invacuo. Purification by flash chromatography (25% EtOAc/hexanes) provided733 mg (78%) of stannyl alcohol 5A as a white solid.

¹ H-NMR (300 MHz, CDCl₃): δ 0.43 (s, 9H), 2.05 (broad s, 1H), 5.11 (s,2H), 7.58-7.71 (m, 4H), 7.79 (d, J=7.7 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H),8.70-8.89 (m, 2H).

EXAMPLE 6 ##STR19## α-(2-nitro-5-methyl-phenyl)-p-bromocinnamic acid (6)

To a mixture of 4-bromobenzaldehyde (19.5 g, 106 mmol) and2-nitro-5-methyl-phenylacetic acid (20.6 g, 106 mmol; J. G. Atkinson et.al., Tetrahedron Lett., 2857, 1979) in 100 ml of acetic anhydride wasadded triethylamine (14.7 ml, 106 mmol) and the resulting reddishsolution was heated at 40° C. for 70 hours. Most of the acetic anhydridewas evaporated under vacuum and the residue was diluted with ethylacetate and washed with sat. NH₄ Cl, H₂ O, and brine. Drying (MgSO₄) andevaporation yielded 37.87 g (99%) of product as a yellow solid which wasused in the next reaction without purification.

¹ H-NMR (300 MHz, d₆ -acetone): δ 2.31 (s, 3H), 7.06 (d, J=8.6 Hz, 2H),7.08 (s, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.44 (d, J=8.40 Hz, 1H), 7.83 (s,1H), 8.13 (d, J=8.4 Hz, 1H).

EXAMPLE 7 ##STR20## Sodium α-(2-amino-5-methyl-phenyl)-p-bromocinnamate(7)

Following the procedure described in Example 2, the nitrophenylcinnamicacid derivative 6 (39.60 g, 110.0 mmol) was reduced with FeSO₄ -NaOH toyield 36.46 g (93%) of amino-carboxylate 7 as a yellow powder which wasused in the next reaction without purification.

¹ H-NMR (200 MHz, 2:1 D₂ O/CD₃ CN): δ 2.47 (s, 3H), 7.03 (bs, 1H), 7.05(d, J=9 Hz, 1H), 7.32 (d, J=9 Hz, 3H), 7.64 (d, J=9 Hz, 2H), 7.82 (s,1H).

EXAMPLE 8 ##STR21## 3-Bromo-7-methyl-phenanthrene-9-carboxylic acid (8)

The amino-carboxylate 7 (36.3 g, 102 mmol) was cyclized following theprocedure described in Example 3 to yield 28.48 g (89%) of crude productas a brown solid. This material was extremely insoluble and wasthoroughly extracted with CH₂ Cl₂ -THF-acetone and filtered. Thefiltrate was evaporated to leave 5.93 g of a brown solid. This "moresoluble" portion of the crude material was utilized in the followingexample.

¹ H-NMR (300 MHz, d₆ -acetone): δ 2.59 (s, 3H), 7.63 (d, J=8.6 Hz, 1H),7.82 (dd, J=8.55, 1.7 Hz, 1H), 8.07 (d, J=8.55 Hz, 1H), 8.59 (s, 1H),8.80 (d, J=8.6 Hz, 1H), 8.99 (d, J=1.7 Hz, 1H).

FAB-MS: M/e=314,316 (M⁺).

EXAMPLE 9 ##STR22## 3-Bromo-7-methyl-phenanthrene (9)

A stirred mixture of 3-Bromo-7-methyl-phenanthrene-9-carboxylic acid(5.50 g, 17.5 mmol) and CuCO₃.Cu(OH)₂.H₂ O (1.5 g) in 50 ml of quinolinewas rapidly heated to 210° C. Gas evolution was observed and the mixturebecame extremely dark. After 10 min the mixture was allowed to cool toroom temperature and was diluted with PhCH₃ --CH₂ Cl₂ (9:1) andfiltered. The filtrate was washed with 1N HCl (2×) and brine. Drying(Na₂ SO₄) and evaporation gave 4.89 g of a brown oil which was flashchromatographed through 450 g of silica gel (10% CH₂ Cl₂ /hexane) toyield 2.63 g (56%) of the title compound as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl₃): δ 7.46 (dd, J=8.4, 1.5 Hz, 1H), 7.6-7.7 (m,4H), 7.70 (d, J=8.52 Hz, 1H), 8.43 (d, J=8.52 Hz, 1H), 8.74 (d, J=1.5Hz, 1H).

FAB-MS: m/e=270,272 (M⁺).

EXAMPLE 10 ##STR23## 3-Bromo-7-(bromomethyl)-phenanthrene (10)

A mixture of 3-bromo-7-methylphenanthrene (2.640 g, 9.736 mmol) andN-bromosuccinimide (1.733 g, 9.736 mmol) in 200 ml of carbontetrachloride was heated to reflux and benzoyl peroxide (25 mg) wasadded. After 2.5 hour a starch-iodide test showed that no NBS remainedand the mixture was cooled to room temperature, washed with water, dried(MgSO₄) and evaporated to give 3.14 g of crude product as a solid. Flashchromatography through 330 g of silica gel (10% CH₂ Cl₂ /hexane) gave2.719 g of a white solid which was recrystallized from 70 ml ofcyclohexane (reflux to RT) to yield 2.061 g (60%) of the title compoundas a white solid, mp 147°-148° C.

¹ H-NMR (300 MHz, CDCl₃): δ 7.64-7.74 (m, 5H), 7.87 (d, J=1.87 Hz, 1H),8.54 (d, J=8.58, 1H), 8.75 (d, J=1.43, 1H).

FAB-MS: m/e=348,350,352 (M⁺).

EXAMPLE 11 ##STR24## 3-Bromo-7-(acetoxymethyl)-phenanthrene (11)

A mixture of 3-bromo-7-(bromomethyl)-phenanthrene (2.249 g, 6.425 mmol)and potassium acetate (1.26 g, 12.8 mmol) in 60 ml of DMF was heated at80° C. for 7 hours. After cooling to RT, the reaction mixture wasdiluted with ethyl ether, washed with water and brine, dried (MgSO₄) andevaporated to give 2.042 g (97%) of the title compound as a white solidwhich was used in the following reaction without purification.

¹ H-NMR (300 MHz, CDCl₃): δ 2.15 (s, 3H), 5.30 (s, 2H), 7.6-7.8 (m, 5H),7.84 (bs, 1H), 8.54 (d, J=8.67 Hz, 1H), 8.75 (d, J=1.7 Hz, 1H).

EXAMPLE 12 ##STR25## 3-Bromo-7-(hydroxymethyl)-phenanthrene (12)

A solution of 3-bromo-7-acetoxymethyl)-phenanthrene (2.042 g, 6.20 mmol)in 50 ml of THF was cooled to 0° C. and a solution of diisobutylaluminumhydride in hexane (1.0M, 14 ml, 14 mmol) was added dropwise. After 30minutes, the solution was cautiously hydrolyzed with 1N HCl and was thendiluted with ethyl acetate and washed successively with 1N HCl, sat.NaHCO₃, H₂ O, and brine. Drying (MgSO₄) and evaporation gave 1.77 g(99%) of the title compound as a white solid which was used in the nextreaction without purification.

¹ H-NMR (300 MHz, CDCl₃): δ 4.91 (s, 2H), 7.6-7.8 (m, 5H), 7.86 (s, 1H),8.56 (d, J=8.67 Hz, 1H), 8.78 (s, 1H).

EXAMPLE 13 ##STR26##3-Bromo-7-(t-butyldimethylsilyloxymethyl)-phenanthrene (13)

Following the procedure described in Example 5,3-bromo-7-(hydroxymethyl)-phenanthrene (1.886 g, 6.568 mmol) wassilylated to yield 2.584 g (98%) of the title compound as a white solid.

¹ H-NMR (300 MHz, CDCl₃): δ 0.143 (s, 6H), 0.979 (s, 9H), 4.95 (s, 2H),7.6-7.8 (m, 5H), 7.82 (bs, 1H), 8.54 (d, J=8.52 Hz, 1H), 8.78 (d,J=1.65, 1H).

FAB-MS: m/e=400,402 (M⁺).

EXAMPLE 14 ##STR27##(3S,4R)-1-(allyloxycarbonyltriphenylphosphoranylidene)methyl-3-[1R-(allyloxycarbonyloxy)ethyl]-4-(3-phenanthrenyl-carbonyl)methylazetidin-2-one(15)

To a mixture of 3-bromophenanthrene (155.7 mg, 0.606 mmol) and magnesiumturnings (22 mg, 0.91 mmol) in 2 ml of THF was added 1,2-dibromoethane(0.010 ml) and the reaction mixture was sonicated briefly in anultrasonic bath to initiate the Grignard formation and was then heatedat 50° C. for 2.25 hours. The above Grignard solution was added dropwiseto a solution of 0.350 g (0.500 mmol) of(3S,4R)-1-(allyloxycarbonyltriphenylphosphoranylidene)methyl-3-[1R-(allyloxycarbonyloxy)ethyl]-4-(2-pyridylthio)-carbonyl)methyl-azetidin-2-one,14, in 2.5 ml of THF at 0° C. After 1 hour, the reaction mixture washydrolyzed with sat. NH₄ Cl solution, diluted with a large volume ofethyl ether, and washed successively with sat. NH₄ Cl, 1N NaOH (2×), H₂O, and brine. Drying (MgSO₄) and evaporation gave a yellow oil which waspurified by flash chromatography through 40 g of silica gel (7:3EtOAc/hexane) to yield 91.3 mg (24%) of the title compound as a yellowfoam.

¹ H-NMR (300 MHz, CDCl₃): inter alia; δ 1.20 (d, J=6.23 Hz, 3H, CH₃).

IR (CHCl₃): 1745 (β-lactam), 1680 (ketone), 1615 cm⁻¹ (yield).

EXAMPLE 15 ##STR28##Allyl-(5R,6S)-2-(3-phenanthrenyl)-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(16)

A solution of the phosphorane 15 (91.0 mg, 0.117 mmol) and a crystal ofhydroquinone in 10 ml of p-xylene was heated to reflux (138° C.). After1 hour, the solution was cooled to room temperature, concentrated underhigh vaccum, and the residual oil was purified by flash chromatographythrough 10 g of silica gel (35% EtOAc/hexane) to yield 51.5 mg (88%) ofthe title compound as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl₃): δ 1.53 (d, J=6.35 Hz, 3H, CH₃), 3.33-3.55 (m,3H, Hl, H6), 4.38 (ddd, J=2.8, 9.2, 9.4 Hz, 1H, H5), 4.6-4.8 (m, 4H,--OCH₂ C═C) 5.08-5.44 (m, 5H, --C═CH₂, H8), 5.75-6.05 (m, 2H, --CH═C),7.55-7.95 (m, 7H, ArH), 8.62 (d, J=8.1 Hz, 1H, ArH), 8.73 (s, 1H, ArH).

IR (CHCl₃): 1780 (β-lactam), 1745 (carbamate), 1725 cm⁻¹ (ester).

UV (CH₃ CN): λmax=237 nm (ε=17,000), 251 (ε=47,000).

EXAMPLE 16 ##STR29## Potassium(5R,6S)-2-(3-phenanthrenyl)-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate(17)

To a solution of the carbapenem 16 (51.0 mg, 0.103 mmol) in 0.6 ml ofethyl acetate at 0° C. were added in sequence a solution of potassium2-ethylhexanoate in ethyl acetate (0.50M, 0.206 ml), a solution of2-ethylhexanoic acid in methylene chloride (1.0M, 0.103 ml),triphenylphosphine (8.0 mg, 0.031 mmol) andtetrakis(triphenylphosphine)palladium (12 mg, 0.010 mmol). The reactionmixture was stirred at 0° C. for 1 hour, and was then pipetted into acentrifuge tube containing cold ethyl ether (2 ml). The precipitate wasisolated by centrifugation, washing twice with ethyl ether. Purificationby reverse-phase preparative TLC (2:1 H₂ O/CH₃ CN) yielded 23.0 mg (54%)of the title compound as an off-white lyophilized solid.

¹ H-NMR (300 MHz, 2:1 D₂ O/CD₃ CN): δ 1.66 (d, J=6.41 Hz, 3H, CH₃), 3.59(dd, J=9.8, 16.7 Hz, 1H, H1a), 3.83 (dd, J=2.7, 6.0 Hz, 1H, H6), 3.96(dd, J=8.6, 16.7 Hz, 1H, H1b), 4.54-4.64 (m, 1H, H8), 4.69 (ddd, J=9.9,9.2, 2.7 Hz, 1H, H5), 7.96-8.14 (m, 3H, ArH), 8.16 (s, 2H, ArH), 8.26(d, J=8.4 Hz, 1H, ArH), 8.33 (dd, J=1.4, 7.7 Hz, 1H, ArH), 9.07 (s, 1H,ArH), 9.10 (d, J=7.7 Hz, 1H, ArH).

IR (KBr): 1750 (β-lactam), 1600 cm⁻¹ (carboxylate). UV (H₂ O): λmax=325nm (ε=16,400).

EXAMPLE 17 ##STR30##(3S,4R)-1-(allyloxycarbonyltriphenylphosphoranylidene)methyl-3-[1R-(allyloxycarbonyloxy)ethyl]-4-[9-(t-butyldimethyl-silyloxymethyl)-3-phenanthrenylcarbonyl]methyl-azetidin-2-one(18)

A solution of 3-bromo-9-(t-butyldimethylsilyloxymethyl)-phenanthrene 5(1.781 g, 4.437 mmol) in 20 ml of THF was cooled to -70° C. and asolution of t-butyllithium in pentane (1.7M, 5.35 ml, 9.1 mmol) wasadded dropwise. The initial yellow solution became a light-greensuspension as the temperature was allowed to warm to -10° C. Uponaddition of a freshly prepared solution of magnesium bromide in THF(0.25M, 20 ml, 5.0 mmol) a bright yellow solution was obtained which wasre-cooled to -70° C. and cannulated gradually into solution of(3S,4R)-1-(allyloxycarbonyltriphenylphosphoranylidene)methyl-3-[1R-(allyloxycarbonyloxy)ethyl]-4-[(2-pyridylthio)carbonyl]methyl-azetidin-2-one(14) (3.145 g, 4.437 mmol) in 25 ml of THF at -70° C. The reactionmixture was allowed to warm gradually to -20° C. during 45 minutes andwas then hydrolyzed with sat. NH₄ Cl and diluted with a large volume ofethyl ether. The organic layer was washed successively with sat. NH₄ Cl,1N NaOH (2×), H₂ O, and brine. Drying (MgSO₄) and evaporation gave anoil which was purified by flash chromatography through 400 g of silicagel (1:1 EtOAc/hexane) to yield 2.869 g (70%) of the title ketone as apale yellow foam.

¹ H-NMR (300 MHz, CDCl₃); inter alia; δ 0.185 (s, 6H, SiMe₂), 1.00 (s,9H, Sit-Bu); 1.18 (d, J=6.3 Hz, 3H, CHCH₃), 5.26 (s, 2H, --CH₂ OSi).

IR (CHCl₃): 1745 (β-lactam), 1680 (ketone), 1615 cm⁻¹ (yield).

FAB-MS: m/e=920 (M+H)

EXAMPLE 18 ##STR31##(3S,4R)-1-(allyloxycarbonyltriphenylphosphoranylidene)methyl-3-[1R-(allyloxycarbonyloxy)ethyl]-4-[9-(hydroxymethyl)-3-phenanthrenylcarbonyl]methyl-azetidin-2-one(19)

A solution of the silyl ether 18 (3.092 g, 3.360 mmol) in 30 ml ofmethanol was cooled to 0° C. and a solution of methanolic sulfuric acid(1.0M, 5.5 ml) was added. After 2.5 hours, the solution was basifiedwith sat. NaHCO₃, and then diluted with a large volume of ethyl acetateand washed successively with sat. NaHCO₃, H₂ O (2×), and brine. Drying(MgSO₄) and evaporation gave an oil which was purified by flashchromatography through 300 g of silica gel (EtOAc) to yield 2.81 g(100%) of the title compound as a yellow foam.

¹ H-NMR (300 MHz, CDCl₃): inter alia; δ 1.19 (d, J=6.16 Hz, 3H, CHCH₃),5.05 (s, 2H, ArCH₂ O).

IR (CHCl₃): 3300-3600 (OH), 1745 (β-lactam), 1680 (ketone), 1615 cm⁻¹(yield).

FAB-MS: m/e=806 (M+H).

EXAMPLE 19 ##STR32##Allyl-(5R,6S)-2-(9-hydroxymethyl-3-phenanthrenyl)-6-[1R-(allyoxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(20)

A solution of the phosphorane 19 (1.488 g, 1.846 mmol) and severalcrystals of p-hydroquinone in 60 ml of p-xylene was heated to reflux(138° C.). After 1.5 hour, the solution was cooled to room temperature,concentrated under high vacuum, and the residual oil was purified byflask chromatography through 150 g of silica gel (3:2 EtOAc/hexane) toyield 0.906 g (93%) of the title carbapenem as a yellow foam.

¹ H-NMR (300 MHz, CDCl₃): δ 1.46 (d, J=6.41 Hz, 3H, CH₃), 3.2-3.4 (m,2H, H1), 3.39 (dd, J=8.2, 2.8 Hz, 1H, H6), 4.26 (dt, J=2.8, 8.9 Hz, 1H,H5), 4.55-4.75 (m, 4H, --OCH₂ C═C), 5.08 (s, 2H, ArCH₂ O--), 5.1-5.4 (m,5H, --C═CH₂, CHCH₃), 5.7-6.0 (m, 2H, --CH═C), 7.4-8.6 (M, 8H, ArH).

IR (CHCl₃): 3300-3600 (OH), 1780 (β-lactam), 1745 (carbamate), 1725 cm⁻¹(ester).

UV (CH₃ CN): λmax=328 nm (ε=15,600), 252 (ε=46,000).

FAB-MS: m/e=528 (M+H).

EXAMPLE 20 ##STR33##Allyl-(5R,6S)-2-(7-hydroxymethyl-3-phenanthrenyl)-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(21)

In an analogous manner to that described in Examples 17-19, but startingwith the bromophenanthrene 13, the carbapenem 21 was obtained as ayellow oil.

¹ H-NMR (300 MHz, CDCl₃): δ 1.50 (d, J=6.29 Hz, 3H, CH₃), 3.28-3.50 (m,3H, H1, H6), 4.33 (ddd, J=2.8, 9.0, 9.7 Hz, 1H, H5), 4.58-4.76 (m, 4H,--OCH₂ C═C), 4.88 (bs, 2H, ArCH₂ O--), 5.06-5.42 (m, 5H, H8, --C═CH₂),5.75-6.00 (m, 2H, --CH═C), 7.54 (dd, J=1.6, 8.3 Hz, 1H), 7.62 (dd,J=1.7, 8.6 Hz, 1H), 7.66-7.76 (ABq, J_(AB) =8.9 Hz, Δν_(AB) =12.5 Hz,2H), 7.82 (d, J=8.3 Hz, 1H), 7.83 (s, 1H), 8.56 (d, J=8.6 Hz, 1H), 8.66(s, 1H).

IR (CHCl₃): 3600 (OH), 1780 (β-lactam), 1745 (carbonate), 1725 cm⁻¹(ester).

UV (CH₃ CN): λmax=328 nm (γ=15,00), 253 nm (ε=47,000).

EXAMPLE 21 ##STR34##p-Nitrobenzyl-(5R,6S)-2-(9-hydroxymethyl-3-phenanthrenyl)-6-[1R-(trimethylsilyloxy)ethyl]-carbapen-2-em-3-carboxylate(23)

A dry 15 mL receiving flask was charged with the bicyclic β-ketoester 22(143 mg; 0.41 mmol) and a magnetic stir bar and the system was purgedwith nitrogen. Two mL of anhydrous tetrahydrofuran (THF) was added andupon dissolution of 22, the reaction vessel was cooled to -78° C. underN₂. Diisopropylamine (0.063 mL, 0.45 mmol) was then added and thestirring was continued for 10 minutes. Trifluoromethanesulfonicanhydride (0.075 mL, 0.45 mmol) was added, followed by stirring for anadditional 15 mins. Triethylamine (0.062 mL, 0.45 mmol) was then added,followed by trimethylsilyltrifluoromethanesulfonate (0.087 mL, 0.45mmol).

While the above reaction was stirred for 20 mins., the organostannane 5A(168 mg, 0.45 mmol), tris(dibenzylideneacetone) dipalladium-chloroform(8.5 mg, 0.0082 mmol) and tris(2,4,6-trimethoxyphenyl)phosphine (17.4mg, 0.033 mmol) were weighed into a single vial and the vial was purgedwith nitrogen. When the above reaction time had elapsed,N-methylpyrrolidinone (2 mL) was added to the initial reaction mixturefollowed by the previously weighed solids. A 0.87M zinc chloride inether solution (0.52 mL, 0.45 mmol) was then added. The low temperaturebath was then removed and the reaction vessel was placed in a luke warmwater bath to allow it to quickly reach ambient temperature. Afterreaching ambient temperature, the mixture was stirred for 13 minutes.The reaction was then quenched by pouring the contents of the flask intoa 125 mL separatory funnel containing diethyl ether, ethyl acetate andwater. The organic phase was separated and washed with water and brine.The organic phase was dried over magnesium sulfate. The mixture was thenfiltered and the solvent removed under vacuum. Flash columnchromatography of the residue (silica gel, 40% ethyl acetate/hexanes)provided 169 mg (68%) of the desired carbapenem 23.

¹ H-NMR (300 MHz, CDCl₃): δ 0.16 (s, 9H), 1.31 (d, J=6.1 Hz, 3H), 2.13(broad s, 1H), 3.29 (dd, J=6.6, 2.0 Hz, 1H), 3.33-3.48 (m, 2H),4.21-4.38 (complex m, 2H), 5.15 (AB_(q), J_(AB) =13.6, Δν_(AB) =53.7 Hz,2H), 5.17 (s, 2H), 7.08 (d, J=8.6 Hz, 2H), 7.45 (dd, J=8.2, 1.6 Hz, 1H),7.56-7.77 (complex m, 6H), 8.05-8.10 (m, 1H), 8.43-8.47 (m, 1H), 8.52(s, 1H).

IR (CHCl₃): 3600(w), 3520-3350(w), 1770(s), 1720(s), 1600(m), 1515(s)cm⁻¹.

UV (CH₃ CN): λmax=252 nm, ε=25,200.

EXAMPLE 22 ##STR35## Potassium(5R,6S)-2-(9-hydroxymethyl-3-phenanthrenyl)-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate(24)

To a solution of the carbapenem 20 (40.4 mg, 0.0766 mmol) in 0.5 ml ofethyl acetate and 0.5 ml of methylene chloride at 0° C. were added insequence a solution of potassium 2-ethylhexanoate in ethyl acetate(0.50M, 0.160 ml), a solution of 2-ethylhexanoic acid in methylenechloride (1.0M, 0.080 ml), triphenylphosphine (6.0 mg, 0.023 mmol), andtetrakis(triphenylphosphine)palladium (9.0 mg, 0.0078 mmol). Thereaction mixture was sonicated briefly in a ultrasonic bath to helpdissolve the palladium catalyst, and was then stirred at 0° C. for 1hour. The reaction mixture was pipetted into a centrifuge tubecontaining cold ethyl ether (2 ml), and the precipitate was isolated bycentrifugation, washing twice with ethyl ether. Purification byreverse-phase preparative TLC (3:1 H₂ O/CH₃ CN) yielded 21 mg (62%) ofthe title compound as an off-white lyophilized solid.

¹ H-NMR (300 MHz, 2:1 D₂ O/CD₃ CN): δ 1.70 (d, J=6.28 Hz, 3H, CH₃), 3.6(dd, J=9.7, 16.6 Hz, 1H, H1a), 3.9 (dd, J=2.6, 6.0 Hz 1H, H6), 4.0 (dd,J=8.8, 16.6 Hz, 1H, Hlb), 4.6-4.8 (m, 2H, H5, H8), 5.5 (s, 2H, ArCH₂--), 8.0-8.2 (m, 3H), 8.2 (s, 1H), 8.3 (d, J=8.36 Hz, 1H), 8.5 dd, J=2,7.5 Hz, 1H), 9.1 (s, 1H), 9.2 (d, J=7.5 Hz, 1H).

IR (KBr): 1750 (β-lactam), 1590 cm-1 (carboxylate).

UV (H₂ O): λmax=327 nm (ε=21,500).

EXAMPLE 23 ##STR36## Potassium(5R,6S)-2-(7-hydroxymethyl-3-phenanthrenyl)-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate(25)

In a analogous manner to that described in Example 22, 39.2 mg (0.0743mmol) of the carbapenem 21 was de-allylated to yield 18.3 mg (56%) ofthe title compound as an off-white lyophilized solid.

¹ H-NMR (300 MHz, 2:1 D₂ O/CD₃ CN): δ 1.68 (d, J=6.35 Hz, 3H, CH₃), 3.60(dd, J=9.6, 16.7 Hz, 1H, H1a), 3.86 (dd, J=2.7, 6.0 Hz, 1H, H6), 3.97(dd, J=8.5, 16.7 Hz, 1H, H1b), 4.56-4.76 (m, 2H, H5, H8), 5.20 (s, 2H,ArCH₂ O--), 8.06 (d, J=8.4 Hz, 2H), 8.18 (s, 2H), 8.27 (d, partiallyobscured, 1H), 8.28 (s, 1H), 9.08 (s, 1H), 9.09 (d, partially obscured,1H)

IR (KBr): 1750 (β-lactam), 1585 cm⁻¹ (carboxylate).

UV (H₂ O): λmax=325 nm (ε=16,700).

What is claimed is:
 1. A compound of the formula: ##STR37## wherein: Ris H or CH₃ ;R^(l) and R² are independently H, CH₃ --, CH₃ CH₂ --,(CH₃)₂ CH--, HOCH₂ --, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, 251 2 CH(OH)--, F₂CHCH(OH)--, F₃ CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;R^(a) are independently selected from the group consisting of hydrogenand the radicals set out below, provided that not more than four R^(a)radicals are other than hydrogen:(a) a trifluoromethyl group: --CF₃ ;(b) a halogen atom: --Br, --Cl, --F, or --I; (c) C₁ -C₄ alkoxy radical:--OC₁₋₄ alkyl, wherein the alkyl is optionally mono-substituted byR^(q), where R^(l) is a member selected from the group consisting of--OH, --OCH₃, --CN, --C(O)NH₂, --OC(O)NH₂, CHO, --OC(O)N(CH₃₃ 3 )₂,--SO₂ NH₂ 45 , --SO₂ N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F, --CF₃, --COOM^(a)(where M^(a) is hydrogen, alkali metal, methyl or phenyl), tetrazolyl(where the point of attachment is the carbon atom of the tetrazole ringand one of the nitrogen atoms is mono-substituted by M^(a) as definedabove) and --SO₃ M^(b) (where M^(b) is hydrogen or an alkali metal);(d)a hydroxy group: --OH; (e) a carbonyloxy radical: --O(C═O)R^(s), whereR^(s) is C₁₋₄ alkyl or phenyl, each of which is optionallymono-substituted by R^(q) as defined above;(f) a carbamoyloxy radical:--O(C═O)N(R^(y))R^(z) where R^(y) and R^(z) are independently H, C₁₋₄alkyl (optionally mono-substituted by R^(q) as defined above), togethera 3- to 5-membered alkylidene radical to form a ring (optionallysubstituted with R^(q) as defined above) or together a 2- to 4-memberedalkylidene radical, interrupted by --O--, --S--, --S(O)-- or --S(O)₂ --,to form a ring (where the ring is optionally mono-substituted with R^(q)as defined above);(g) a sulfur radical: --S(O)_(n) --R^(s) where n=0-2,and R^(s) is defined above; (h) a sulfamoyl group: --SO₂ N(R^(y))R^(z)where R^(y) and R^(z) are as defined above; (i) azido: N₃ (j) aformamido group: --N(R^(t))(C═O)H, where R^(t) is H or C₁₋₄ alkyl, andthe alkyl thereof is optionally mono-substituted by R^(q) as definedabove;(k) a (C₁ -C₄ alkyl)carbonylamino radical: --N(R^(t))(C═O)C₁₋₄alkyl, where R^(t) is as defined above, and the alkyl group is alsooptionally mono-substituted by R^(q) as defined above; (l) a (C₁ -C₄alkoxy) carbonylamino radical: --N(R^(t))(C═O)OC₁₋₄ alkyl, where R^(t)is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above; (m) a ureido group:--N(R^(t))(C═O)N(R^(y))R^(z) where R^(t), R^(y) and R^(z) are as definedabove; (n) a sulfonamido group: --N(R^(t))SO₂ R^(s), where R^(s) andR^(t) are as defined above; (o) a cyano group: --CN; (p) a formyl oracetalized formyl radical: --(C═O)H or --CH(OCH₃)₂ ; (q) (C₁ -C₄alkyl)carbonyl radical wherein the carbonyl is acetalized: --C(OCH₃)₂C₁₋₄ alkyl, where the alkyl is optionally mono-substituted by R^(q) asdefined above; (r) carbonyl radical: --(C═O)R^(s), where R^(s) is asdefined above; (s) a hydroximinomethyl radical in which the oxygen orcarbon atom is optionally substituted by a C₁ -C₄ alkyl group:--(C═NOR^(z))R^(y) where R^(y) and R^(z) are as defined above, exceptthey may not be joined together to form a ring; (t) a (C₁ -C₄ alkoxy)carbonyl radical: --(C═O)OC₁₋₄ alkyl, where the alkyl is optionallymono-substituted by R^(q) as defined above; (u) a carbamoyl radical:--(C═O)N(R^(y))R^(z) where R^(y) and R^(z) are as defined above; (v) anN-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical in which thenitrogen atom may be additionally substituted by a C₁ -C₄ alkyl group:--(C═O)--N(OR^(y))R^(z) where R^(y) and R^(z) are as defined above,except they may not be joined together to form a ring; (w) athiocarbamoyl group: --(C═S)N(R^(y))(R^(z)) where R^(y) and R^(z) are asdefined above; (x) carboxyl: --COOM^(b), where M^(b) is as definedabove; (y) thiocyanate: --SCN; (z) trifluoromethylthio: --SCF₃ ; (aa)tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above; (ab) an anionic function selected from the groupconsisting of: phosphono [P═O(OM^(b))₂ ]; alkylphosphono{P═O(OM^(b))--[O(C₁ -C₄ alkyl)]}; alkylphosphinyl [P═O(OM^(b))--(C₁ -C₄alkyl)]; phosphoramido [P═O(OM^(b))N(R^(y))R^(z) and P═O(OM^(b))NHR^(x)]; sulfino (SO₂ M^(b)); sulfo (SO₃ M^(b)); acylsulfonamides selectedfrom the structures CONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂NM^(b) CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where R^(x) is phenyl orheteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, in which a carbon atom is the point ofattachment, in which one of the carbon atoms has been replaced by anitrogen atom, in which one additional carbon atom is optionallyreplaced by a heteroatom selected from O or S, and in which from 1 to 2additional carbon atoms are optionally replaced by a nitrogenheteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), as defined above; M^(b) is as defined above;and R^(y) and R^(z) are as defined above;(ac) C₅ -C₇ cycloalkyl group inwhich one of the carbon atoms in the ring is replaced by a heteroatomselected from O, S, NH or N(C₁ -C₄ alkyl) and in which one additionalcarbon atom may be replaced by NH or N(C₁ -C₄ alkyl), and in which atleast one carbon atom adjacent to each nitrogen heteroatom has both ofits attached hydrogen atoms replaced by one oxygen thus forming acarbonyl moiety and there are one or two carbonyl moieties present inthe ring; (ad) C₂ -C₄ alkenyl radical, optionally mono-substituted byone of the substituents (a) to (ac) above and phenyl which is optionallysubstituted by R^(q) as defined above; (ae) C₂ -C₄ alkynyl radical,optionally mono-substituted by one of the substituents (a) to (ac)above; (af) C₁ -C₄ alkyl radical; (ag) C₁ -C₄ alkyl mono-substituted byone of the substituents (a)-(ac) above; (ah) a 2-oxazolidinonyl moietyin which the point of attachment is the nitrogen atom of theoxazolidinone ring, the ring oxygen atom is optionally replaced by aheteroatom selected from --S-- and NR^(t) (where R^(t) is as definedabove) and one of the saturated carbon atoms of the oxazolidinone ringis optionally mono-substituted by one of the substituents (a) to (ag)above; M is selected from:(i) hydrogen; (ii) a pharmaceuticallyacceptable esterifying group or removable carboxyl protecting group; or(iii) an alkali metal or other pharmaceutically acceptable cation. 2.The compound of claim 1 wherein R¹ is hydrogen and R² is (R)--CH₃CH(OH)-- or (R)--CH₃ CH(F)--.
 3. The compound of claim 2 wherein atleast one R^(a) in either the 1-, 9-, or 10-position of saidphenanthrene is other than hydrogen.
 4. The compound of claim 2 wherein,in total, up to two R^(a) substituents in either the 1-, 9- or10-position of said phenanthrene is other than hydrogen.
 5. A compoundaccording to claim 2 wherein R^(a) other than hydrogen is selected fromthe group consisting of:

    ______________________________________                                        --OCH.sub.3        --OCH.sub.2 CO.sub.2 Na                                    --OCH.sub.2 CH.sub.2 OH                                                                          --CF.sub.3                                                 --F                --Cl                                                       --Br               --I                                                        --OH               --OCOCH.sub.3                                              --OCONH.sub.2      --SCH.sub.3                                                --SOCH.sub.3       --SO.sub.2 CH.sub.3                                        --SCH.sub.2 CH.sub.2 OH                                                                          --SOCH.sub.2 CH.sub.2 OH                                   --SO.sub.2 NH.sub.2                                                                              --SO.sub.2 N(CH.sub.3).sub.2                               --NHCHO            --NHCOCH.sub.3                                             --NHCO.sub.2 CH.sub.3                                                                            --NHSO.sub.2 CH.sub.3                                      --CN               --CHO                                                      --COCH.sub.3       --COCH.sub.2 OH                                            --CH═NOH       --CH═NOCH.sub.3                                        --CH═NOCH.sub.2 CO.sub.2 H                                                                   --CH═NOCMe.sub.2 CO.sub.2 H                            --CH═NOCMe.sub.2 CO.sub.2 Me                                                                 --CO.sub.2 CH.sub.2 CH.sub.2 OH                            --CONH.sub.2       --CONHCH.sub.3                                             --CON(CH.sub.3).sub.2                                                                            --CONHCH.sub.2 CN                                          --CONHCH.sub.2 CONH.sub.2                                                                        --CONHCH.sub.2 CO.sub.2 H                                  --CONHOH           --CONHOCH.sub.3                                            tetrazolyl         --CO.sub.2 Na                                              --SCF.sub.3        --PO.sub.3 NaH                                             --CONHSO.sub.2 Ph  --CONHSO.sub.2 NH.sub.2                                    --SO.sub.3 Na      --SO.sub.2 NHCN                                            --SO.sub.2 NHCONH.sub.2                                                                          --CH═CHCN                                              --CH═CHCONH.sub.2                                                                            --CH═CHCO.sub.2 Na                                     --C.tbd.C--CONH.sub.2                                                                            --C.tbd.C--CN                                              --CH.sub.2 OH      --CH.sub.2 N.sub.3                                         --CH.sub.2 CO.sub.2 Na                                                                           SO.sub.2 CH.sub.2 CH.sub.2 OH, and                         --CH.sub.2 I.                                                                 ______________________________________                                    


6. A compound of the formula: ##STR38## wherein R, R¹, R², M and R^(a)are selected from the group consisting of

    __________________________________________________________________________                                        Ra                                        # R   R.sup.1                                                                          R.sup.2   M   R.sup.a      position                                  __________________________________________________________________________     1                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K+                                                                              --OCH.sub.3  9,10                                       2                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K+                                                                              --OCH.sub.2 CO.sub.2 Na                                                                    1                                          3                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --H --OCH.sub.2 CH.sub.2 OH                                                                    9                                          4                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --CF.sub.3   1                                          5                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --F          1                                          6                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --Cl         9                                          7                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --Br         10                                         8                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --F          1,7,9,10                                   9                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --OH         9,10                                      10                                                                              --CH.sub.3                                                                        --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --H --OCOCH.sub.3                                                                              9                                         11                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --OCONH.sub.2                                                                              9                                         12                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --SCH.sub.3  1                                         13                                                                              --H --H                                                                              (R)--CH(F)CH.sub.3                                                                      --K.sup.+                                                                         --SOCH.sub.3 1                                         14                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --SO.sub.2 CH.sub.3                                                                        1                                         15                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --SCH.sub.2 CH.sub.2 OH                                                                    1                                         16                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --SOCH.sub.2 CH.sub.2 OH                                                                   9                                         17                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --SCH.sub.2 CONH.sub.2                                                                     1                                         18                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --SO.sub.2 NH.sub.2                                                                        1                                         19                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --SO.sub.2 N(CH.sub.3).sub.2                                                               7,9                                       20                                                                              --H --H                                                                              --CF.sub.2 CH.sub.3                                                                     --K.sup.+                                                                         --NHCHO      10,8                                      21                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --NHCOCH.sub.3                                                                             1                                         22                                                                              --H --H                                                                              (R)-- CH(OH)CH.sub.3                                                                    --H --NHCO.sub.2 CH.sub.3                                                                      10                                        23                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --NHSO.sub.2 CH.sub.3                                                                      1                                         24                                                                              --H --H                                                                              (R)--CH(F)CH.sub.3                                                                      --K.sup.+                                                                         --CN         1                                         25                                                                              --H --H                                                                              (R)--CH(F)CH.sub.3                                                                      --K.sup.+                                                                         --CHO        1                                         26                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --COCH.sub.3 10                                        27                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --COCH.sub.2 OH                                                                            9                                         28                                                                              --CH.sub.3                                                                        --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CH═NOH 6                                         29                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CH═NOCH.sub.3                                                                        1                                         30                                                                              --CH.sub.3                                                                        --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --H --CH═NOCH.sub.2 CO.sub.2 H                                                             9                                         31                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CH═NOCMe.sub.2 CO.sub.2 Na                                                           7                                         32                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CH═NOCMe.sub.2 CO.sub.2 Me                                                           1                                         33                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --CO.sub. 2 CH.sub.2 CH.sub.2 OH                                                           1                                         34                                                                              --H --H                                                                              (R)--CH(F)CH.sub.3                                                                      --K.sup.+                                                                         --CONH.sub.2 1,9                                       35                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --CONHCH.sub.3                                                                             9                                         36                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --CON(CH.sub.3).sub.2                                                                      10                                        37                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --CONHCH.sub.2 CN                                                                          1                                         38                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --CONHCH.sub.2 CONH.sub.2                                                                  l                                         39                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --CONHCH.sub.2 CO.sub.2 H                                                                  1                                         40                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CONHOH     1                                         41                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CONHOCH.sub.3                                                                            9                                         42                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        tetrazolyl   1                                         43                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CO.sub.2 Na                                                                              9                                         44                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --SCF.sub.3  1                                         45                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --H --PO.sub.3NaH                                                                              1                                         46                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CONHSO.sub.2 Ph                                                                          10                                        47                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CONHSO.sub.2 NH.sub.2                                                                    1                                         48                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --SO.sub.3 Na                                                                              1                                         49                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --SO.sub.2 NHCN                                                                            1                                         50                                                                              --H --H                                                                              (R)--CH(F)CH.sub.3                                                                      --Na.sup.+                                                                        --SO.sub.2 NHCONH.sub.2                                                                    1                                         51                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CH═CHCN                                                                              1                                         52                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CH═CHCONH.sub.2                                                                      1                                         53                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CH═CHCO.sub.2 Na                                                                     9                                         54                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --C.tbd.C--CONH.sub.2                                                                      l                                         55                                                                              --CH.sub.3                                                                        --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --C.tbd.C--CN                                                                              9                                         56                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --CH.sub.2 OH                                                                              5                                         57                                                                              --H -- H                                                                             (R)--CH(OH)CH.sub.3                                                                     --K.sup.+                                                                         --CH.sub.2 N.sub.3                                                                         9                                         58                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                     --Na.sup.+                                                                        --CH.sub.2 CO.sub.2 Na                                                                     9                                         59                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CN         1                                         60                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CN         7                                         61                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CN         8                                         62                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CN         9                                         63                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CN         10                                        64                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CHO        5                                         65                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CHO        6                                         66                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CHO        7                                         67                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CHO        8                                         68                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CHO        9                                         69                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CHO        10                                        70                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CONH.sub.2 1                                         71                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CONH.sub.2 7                                         72                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup. +                                                                          --CONH.sub.2 8                                         73                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CONH.sub.2 9                                         74                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CONH.sub.2 10                                        75                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CH═NOH 1                                         76                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CH═NOH 7                                         77                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CH═NOH 8                                         78                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CH═NOH 9                                         79                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CH═NOH 10                                        80                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CH.sub.2 OH                                                                              7                                         81                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --CH.sub.2 OH                                                                              9                                         82                                                                              H   H  (R)--CH(OH)CH.sub.3                                                                     K.sup.+                                                                           --H          --                                        __________________________________________________________________________


7. A compound of the formula: ##STR39## wherein R, R¹, R², M and R^(a)are selected from the group consisting of:

    __________________________________________________________________________    # R   R.sup.                                                                           R.sup.2    M  R.sup.a                                                __________________________________________________________________________    1 --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          1-F    9-CH.sub.2 OH                                   2 --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          1-F    9-CHO                                           3 --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          1-SOCH.sub.3                                                                         9-CHO                                           4 --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          1-SOCH.sub.3                                                                         7-CHO                                           5 --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          1-CN   7-SOCH.sub.3                                    6 --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          1-CONH.sub.2                                                                         9-CH.sub.2 OH                                   7 --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          1-CONH.sub.2                                                                         9-SOCH.sub.3                                    8 --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          1-CN   7-CH.sub.2 OH                                   9 --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          9-CHO  10-OH                                           10                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          1-CONH.sub.2                                                                         9-CHO                                           11                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          1-CN   9-CO.sub.2 K                                    12                                                                              --H --H                                                                              (R)--CH(OH)CH.sub.3                                                                      K.sup.+                                                                          1-CONH.sub.2                                                                         10-OH                                           __________________________________________________________________________


8. A composition comprising a pharmaceutically acceptable carrier andfrom 0.1% to about 99% by weight of active material of claim
 1. 9. Acomposition according to claim 8 which further comprises an inhibitorilyeffective amount of a DHP inhibitor.
 10. A composition according toclaim 9 wherein said DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptanoicacid.
 11. A method for treating bacterial infection in mammalscomprising administering a pharmaceutical composition comprising aneffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier therefor.
 12. A method according to claim 11 whichfurther comprises administering an inhibitorily effective amount of aDHP inhibitor.
 13. A method according to claim 12 wherein said DHPinhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptanoicacid.